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Ligandless Heck Coupling between a Halogenated Aniline and Acrylonitrile Catalyzed by Pd/C: Development and Optimization of an Industrial-Scale Heck Process for the Production of a Pharmaceutical Intermediate

2008; American Chemical Society; Volume: 12; Issue: 3 Linguagem: Inglês

10.1021/op8000383

1520-586X

Didier Schils, Fred Stappers, Geoffrey Solberghe, Richard van Heck, Michelle Coppens, Dirk van den Heuvel, Peter Van der Donck, Tom Callewaert, Frank Meeussen, Erika De Bie, Kristof Eersels, Ellen Schouteden,

Cyclopropane Reaction Mechanisms

The aniline derivative 3 is a key building block of rilpivirine (TMC278) 2, a new potent NNRTI compound under clinical evaluation. In this paper we describe the development of a new synthesis of 3 based on a Heck coupling between a halogenated aniline and acrylonitrile using low loading of Pd/C (0.5 mol %) as catalyst. This resulted in a process which has been successfully transferred into production on 2400 mol-scale (6000 L reactor)